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Preface

This risk-benefit analysis is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify potential rejuvenation therapies and systematically evaluate their risks, benefits, and associated therapeutic protocols to create transparency.

Section 1: Overview 

Motivation

NAD+ is a pyridine nucleotide found in all living cells. It plays an important role in energy metabolism and is a substrate for several enzymes (including those involved in DNA repair). NAD+ levels may decline markedly with age (Massudi et al., 2012; Clement et al., 2019; Zhu et al., 2011) and restoring those levels to a youthful state is believed to have beneficial effects on health and longevity. 

Key Questions 

This analysis seeks to answer the following questions:

• Which health and/or longevity benefits result from raising NAD+ levels in humans? 

• Which risks are involved in raising NAD+ levels (general and method-specific)?

• What are the potential risk mitigation strategies?

• Which method or combination of methods is most effective in raising NAD+ levels?

• Which of the available methods are safe for use? 

• What is the best therapeutic protocol available at the moment?  

Impatient readers may choose to skip directly to  Section 6  for the conclusion and tips on practical application. 

Section 2: Methods

Analytic model

The RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development ( Sarac et al., 2012 ). 

Literature search

A literature search was conducted on Pubmed and the Cochrane Library using the search terms shown in Table 1 . Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms.

The inclusion criteria for human studies were necessarily broad as there is a scarcity of evidence. We chose to include any trial that was conducted in humans using NAD precursors other than niacin/nicotinic acid as the majority of those trials used cholesterol-lowering as the primary endpoint and don't mention NAD+ levels. Additionally, niacin/NA results in uncomfortable flushing in many people at relatively low doses and is therefore not generally used for NAD+ restoration therapy. 

Table 1: Literature Search 

Recommended Reading

The following sites offer information on NAD+ at a consumer level and are useful as an introduction to the topic:

•  

  • NAD Popular - alivebynature.com

  • An Interview with Mike Bonkowski – NAD+ and Aging - leafscience.org

  • NAD+ Repletion Shows Potential Against Aging - leafscience.org
    

  • NAD An Emerging Framework For Life Extension - anti-agingfirewalls.com

Abbreviation list

Section 3: Existing evidence

Summary of results from clinical trials (humans)

We identified 41 completed clinical trials and 29 that are ongoing ( aboutnad.com). The majority of published clinical trials have been performed for dermatological conditions and used NAM as the study compound.  Only two human studies used NAD+ as the study compound, one as i.v. therapy and the other topically. The other trials examined various precursors that have been shown to raise NAD+ levels. We identified a case report series but were unable to find any RCTs on systemic NAD+ i.v. or patch therapies. 

Table 2: Clinical Trials

Summary of results from preclinical trials (animals & in vitro )

Due to the lack of evidence from clinical trials, a decision was made to include results from preclinical studies (animals/in vitro) in order to gain more data to aid in the assessment of the risk/benefit ratio. We identified 145 preclinical trials with potentially clinically relevant risk/benefit criteria. The majority of the studies were conducted in rodents and studies on NAD+ itself as well as all known precursors exist.

Table 3: Preclinical trials 

Section 4: Risk-Benefit Analysis

Decision Model

Risk and benefit criteria

The decision profile is made of up risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and include the type, magnitude, and duration of the benefit as well as its perceived importance to the patient. The risk criteria are organized by category, type, severity, frequency, detectability, and mitigation. All are assigned numerical values: 

1 = low

2 = moderate

3 = high

The numerical values for both risk and benefit criteria are then summarized serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). Each benefit and risk criteria is assigned a weight/importance of 1 (low) 2 (medium) or 3 (high).

Weighting is independent of data sets and the final weights are based on consensus with justification based on the preceding columns of the table.

Score

Each category is assessed according to the performance of NAD+ restoration therapy against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior) and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, whether it came from human or animal studies and whether methodological flaws, conflicting studies, or conflicts of interest (funding) by the authors are present. Human evidence is initially assigned a score of "1", evidence from rodent studies, "2", and in vitro or lower animal studies, "3". The uncertainty score is then adjusted by upgrading or downgrading using the above-mentioned criteria. 

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted using the uncertainty score. Weighted scores may be upgraded where the uncertainty of the evidence is low or downgraded where the uncertainty of the evidence is high. 

Benefit assessment 

Table 4: Benefit assessment